Anti-tumor drug, pharmaceutical composition, and use thereof

Abstract

The present invention provides an anti-tumor compound, a pharmaceutical composition, and a use thereof. Specifically, the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof. The anti-tumor compound provided by the present invention has one or more of the following effects, comprising: 1) having in vitro antiproliferative activity against tumor cells; 2) having plasma stability; 3) having an anti-transporter transport capacity; 4) having an in vivo tumor inhibition effect; 5) having the bystander effect; and 6) having good in vivo safety.

Description

An antitumor drug, a pharmaceutical composition and its application

[0001] This application claims priority to Chinese patent application 2025101269263, filed on January 27, 2025. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to an antitumor drug, a pharmaceutical composition, and its application. Background Technology

[0003] Antibody-drug conjugates (ADCs) link monoclonal antibodies or antibody fragments to biologically active cytotoxic agents via stable chemical linker compounds. This fully leverages the specificity of antibodies in binding to antigens on the surface of both normal and tumor cells, as well as the high efficiency of cytotoxic agents, while avoiding the lower efficacy of the former and the excessive toxicity of the latter. This means that, compared to traditional chemotherapy drugs, antibody-drug conjugates can bind to tumor cells more precisely and reduce the impact on normal cells.

[0004] Camptothecin derivatives exhibit antitumor activity by inhibiting topoisomerase I. The use of camptothecin derivative ethanotecan in antibody-drug conjugates (ADCs) has been reported in the literature, but further development of more effective ADC drugs is still needed in this field. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the deficiency of insufficient types of camptothecin derivative compounds for anti-tumor purposes in the prior art, and to provide a compound with good anti-tumor activity, high stability and good safety, and its application.

[0006] The present invention solves the above-mentioned technical problems through the following technical solution:

[0007] This invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

[0008] in,

[0009] R 2 H, deuterium, halogen, NR n1 R n2 hydroxyl group, C 1-8 Alkyl or with one or more R 2-1 Replacement C 1-8 Alkyl; R 2-1 For deuterium, halogen, NR n1 R n2 or hydroxyl groups;

[0010] Y is -LR0 ;R 0 For OH or NR n3 R n4 ;R n3 and R n4 Independently H or C 1-8 alkyl;

[0011] L is L 0 or -(L 1 -O) m -L 2 -;

[0012] L 0 L 1 and L 2 Selected independently from C 1-8 alkylene or by one or more R c Replacement C 1-8 Alkylene; m is 1, 2, or 3;

[0013] R c Independent of deuterium, halogen, NR n1 R n2 or hydroxyl groups;

[0014] R n1 and R n2 Independently H or C 1-8 alkyl;

[0015] R 1 R 3 The definition of X is as follows:

[0016] Option 1:

[0017] R 1 H, deuterium, halogen, NR n1 R n2 hydroxyl group, C 1-8 Alkyl or with one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 For deuterium, halogen, NR n1 R n2 or hydroxyl groups;

[0018] R 3 For S or O;

[0019] X is -CR x-1 R x-2 -、-O-、-S-、-P(=O)(OH)O-* or Ring A is a 4-10 membered heterocyclic alkyl group. In addition to the N atom attached to it, ring A contains 0, 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S; n is 0, 1, 2 or 3; and the * end is attached to Y.

[0020] R b Halogen, deuterium, oxo group, hydroxyl group, NR n1 R n2 C 1-8 Alkyl, C 1-8 Alkyl groups or those with one or more R groups b-1 Replacement C 1-8 alkyl;

[0021] R x-1 and R x-2 Independently for H and C 1-8 Alkyl or with one or more R x-1-1 Replacement C 1-8 Alkyl; or, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 cycloalkyl;

[0022] R x-1-1 R a-1 and R b-1 Independent of deuterium, halogen, NR n1 R n2 or hydroxyl groups;

[0023] R n1 and R n2 Independently H or C 1-8 alkyl;

[0024] Option 2:

[0025] R 1 H, deuterium, halogen, NR n1 R n2 hydroxyl group, C 1-8 Alkyl or with one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 For deuterium, halogen, NR n1 R n2 or hydroxyl groups;

[0026] R 3 For S or O;

[0027] X is -CR x-1 R x-2 -、-NR a -、-O-、-S-、-P(=O)(OH)O-* or Ring A is a 4-10 membered heterocyclic alkyl group. In addition to the N atom attached to it, ring A contains 0, 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S; n is 0, 1, 2 or 3; and the * end is attached to Y.

[0028] R a For deuterium, C 1-8 Alkyl or with one or more R a-1 Replacement C 1-8 alkyl;

[0029] R b Halogen, deuterium, oxo group, hydroxyl group, NR n1 R n2 C 1-8 Alkyl, C 1-8 Alkyl groups or those with one or more R groups b-1 Replacement C 1-8 alkyl;

[0030] R x-1 and R x-2 Independently for H and C 1-8 Alkyl or with one or more R x-1-1 Replacement C 1-8 Alkyl; or, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 cycloalkyl;

[0031] R x-1-1 R a-1 and R b-1 Independent of deuterium, halogen, NR n1 R n2 or hydroxyl groups;

[0032] R n1 and R n2 Independently H or C 1-8 alkyl;

[0033] Option 3:

[0034] R 1 H, deuterium, halogen, NR n1 R n2 hydroxyl group, C 1-8 Alkyl or with one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 For deuterium, halogen, NR n1 R n2 or hydroxyl groups;

[0035] R 3 S;

[0036] X is -CR x-1 R x-2 -、-NH-、-NR a -、-O-、-S-、-P(=O)(OH)O-* or Ring A is a 4-10 membered heterocyclic alkyl group. In addition to the N atom attached to it, ring A contains 0, 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S; n is 0, 1, 2 or 3; and the * end is attached to Y.

[0037] R a For deuterium, C 1-8 Alkyl or with one or more R a-1 Replacement C 1-8 alkyl;

[0038] R b Halogen, deuterium, oxo group, hydroxyl group, NR n1 R n2 C 1-8 Alkyl, C 1-8 Alkyl groups or those with one or more R groups b-1 Replacement C 1-8 alkyl;

[0039] R x-1 and R x-2 Independently for H and C 1-8 Alkyl or with one or more R x-1-1 Replacement C 1-8 Alkyl; or, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 cycloalkyl;

[0040] R x-1-1 R a-1 and R b-1 Independent of deuterium, halogen, NR n1 R n2 or hydroxyl groups;

[0041] R n1 and R n2 Independently H or C 1-8 alkyl;

[0042] Option 4:

[0043] R 1 H, deuterium, halogen, NR n1 R n2 hydroxyl group or one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 For deuterium, halogen, NRn1 R n2 or hydroxyl groups;

[0044] R 3 For S or O;

[0045] X is -CR x-1 R x-2 -、-NH-、-NR a -、-O-、-S-、-P(=O)(OH)O-* or Ring A is a 4-10 membered heterocyclic alkyl group. In addition to the N atom attached to it, ring A contains 0, 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S; n is 0, 1, 2 or 3; and the * end is attached to Y.

[0046] R a For deuterium, C 1-8 Alkyl or with one or more R a-1 Replacement C 1-8 alkyl;

[0047] R b Halogen, deuterium, oxo group, hydroxyl group, NR n1 R n2 C 1-8 Alkyl, C 1-8 Alkyl groups or those with one or more R groups b-1 Replacement C 1-8 alkyl;

[0048] R x-1 and R x-2 Independently for H and C 1-8 Alkyl or with one or more R x-1-1 Replacement C 1-8 Alkyl; or, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 cycloalkyl;

[0049] R x-1-1 R a-1 and R b-1 Independent of deuterium, halogen, NR n1 R n2 or hydroxyl groups;

[0050] R n1 and R n2 Independently H or C 1-8 alkyl.

[0051] In some embodiments, certain groups in the compound of Formula I or its pharmaceutically acceptable salt are defined as follows, and groups not mentioned are as described in any embodiment of the invention (hereinafter referred to as "in some embodiments"), wherein C 1-8 Alkyl groups are independently C 1-6 Alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and for example, methyl or ethyl.

[0052] In some embodiments, the halogen is independently F, Cl, Br, or I; for example, F or Cl; or F for example.

[0053] In some embodiments, the “4-10 membered heterocyclic alkyl” is a 4-8 membered heterocyclic alkyl; for example, a 5-6 membered heterocyclic alkyl.

[0054] In some embodiments, the "4-10 membered heterocyclic alkyl group having one, two, or three heteroatoms selected from N, O, and S" is a 4-10 membered heterocyclic alkyl group having one, two, or three N atoms.

[0055] In some embodiments, the "4-10 membered heterocyclic alkyl group having one, two or three heteroatoms selected from N, O, and S" means a 4-10 membered heterocyclic alkyl group having one or two heteroatoms selected from N, O, and S.

[0056] In some implementations, the C 1-8 Alkyl groups are independently C 1-6 Alkyl groups; for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, and again, for example, methoxy or ethoxy.

[0057] In some implementation schemes, R 2 It is a halogen.

[0058] In some implementation schemes, R 0 It is OH.

[0059] In some implementations, L is L 0 .

[0060] In some implementations, L 0 C 1-8 Alkylene.

[0061] In some implementation schemes, in Scheme 1, R 1 C 1-8 Alkyl; for example, methyl.

[0062] In some implementation schemes, in Scheme 1, R 3 It can be S or O.

[0063] In some implementation schemes, in Scheme 1, X is -CR x-1 R x-2 -

[0064] In some implementation schemes, in Scheme 1, R x-1 and R x-2 Independently for C 1-8 Alkyl; for example, R x-1 and R x-2 Independently methyl; or, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 Cycloalkyl; for example, R x-1 R x-2 Together with the C atoms they are attached to, they form cyclopropyl groups.

[0065] In some implementation schemes, in Scheme 2, R 1 C 1-8 Alkyl or with one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 It is deuterium.

[0066] In some implementation schemes, in Scheme 2, R 3 It can be S or O.

[0067] In some implementation schemes, in Scheme 2, X is -NR a -

[0068] In some implementation schemes, in Scheme 2, R a C 1-8 Alkyl; for example, C 1-6 Alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and for example, methyl or ethyl.

[0069] In some implementation schemes, in Scheme 3, R 1 C 1-8 alkyl.

[0070] In some implementation schemes, in Scheme 3, R 3 Let it be S.

[0071] In some implementation schemes, in Scheme 3, X is -CR x-1 R x-2 -or-NR a -

[0072] In some implementation schemes, in Scheme 3, R a C 1-8Alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and for example, methyl or ethyl.

[0073] In some implementation schemes, in Scheme 3, R x-1 and R x-2 Independently for C 1-8 Alkyl; for example, R x-1 and R x-2 Independently methyl; or, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 Cycloalkyl; for example, R x-1 R x-2 Together with the C atoms they are attached to, they form cyclopropyl groups.

[0074] In some implementation schemes, in scheme four, R 1 For one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 It is deuterium.

[0075] In some implementation schemes, in scheme four, R 3 It can be S or O.

[0076] In some implementation schemes, in scheme four, X is -CR x-1 R x-2 -or-NR a -

[0077] In some implementation schemes, in scheme four, R a C 1-8 Alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and for example, methyl or ethyl.

[0078] In some implementation schemes, in scheme four, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 Cycloalkyl; for example, R x-1 R x-2 Together with the C atoms they are attached to, they form cyclopropyl groups.

[0079] In some implementation schemes, R 1 It is methyl or trideuterated methyl.

[0080] In some implementation schemes, R 2 It is F.

[0081] In some implementation schemes, X is

[0082] Y is

[0083] In some embodiments, the compound shown in Formula I is a compound shown in Formula I-1:

[0084] Among them, R 0 L 0 R x-1 R x-2 R 1 R 2 and R 3 The definition is as stated in the previous item.

[0085] In some embodiments, the compound shown in Formula I is a compound shown in Formulas I-2:

[0086] Among them, R 0 L 0 R a R 1 R 2 and R 3 The definition is as stated in the previous item.

[0087] In some embodiments, the compound shown in Formula I is a compound shown in Formulas I-3:

[0088] Among them, R 0 L 0 X, R 1 and R 2 The definition is as stated in the previous item.

[0089] In some embodiments, the compound shown in Formula I is a compound shown in Formulas I-4:

[0090] Among them, R 0 L 0 X, R 1 and R 3 The definition is as stated in the previous item.

[0091] The present invention also provides any of the following compounds or pharmaceutically acceptable salts thereof:

[0092] This invention provides a pharmaceutical composition comprising:

[0093] (1) Any of the above compounds or their pharmaceutically acceptable salts, and

[0094] (2) Pharmaceutically acceptable excipients.

[0095] The present invention also provides the use of the above-described compound as shown in Formula I or a pharmaceutically acceptable salt thereof, the above-described compound or a pharmaceutically acceptable salt thereof, and the above-described pharmaceutical composition in the preparation of a medicament for treating tumors or tumor-related diseases.

[0096] Terminology Explanation

[0097] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0098] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1 to C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0099] The term "alkoxy" refers to the group R. X -O-, where R X It is an alkyl group as defined above.

[0100] The term "heterocyclic alkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 4 to 12), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which can be monocyclic, bridged, or spirocyclic, and each ring is saturated. A bridged ring is a polycyclic ring that shares two or more atoms between monocyclic rings. A spirocyclic ring is a polycyclic ring that shares one atom between monocyclic rings. Heterocyclic alkyl groups include, but are not limited to, nitrogen-containing heterocyclic butyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, and piperidinyl.

[0101] The "-" at the end of a group indicates that the group is connected to other segments in the molecule through that site. For example, -O- indicates that the oxygen atom is connected to other segments in the molecule at both ends.

[0102] In structural fragments This refers to the connection between this structural segment and other segments in the molecule through this site. For example, It refers to hydroxyethyl.

[0103] The term "multiple" refers to 2, 3, 4, or 5.

[0104] “C3-C n "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to n cyclic carbon atoms and zero heteroatoms, where n is an integer greater than 3. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptanetrienyl, etc.

[0105] When any variable (e.g., group R) 1-1When these terms appear multiple times in the definition of a compound, their definitions are independent and do not affect each other. For example, a compound defined by three R's... 1-1 Replacement C 1-8 Alkyl refers to C 1-8 Alkyl groups will be formed by 3 Rs 1-1 Replace, 3 R 1-1 The definitions are independent of each other and do not affect each other.

[0106] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, and ammonium salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, sulfate, and mesylate salts. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.

[0107] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009) for details.

[0108] The term “treatment” refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that triggers the disease; or (3) slowing the development of one or more biological manifestations of a disease.

[0109] The term "prevention" refers to reducing the risk of developing a disease.

[0110] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0111] The reagents and raw materials used in this invention are all commercially available.

[0112] The positive and progressive effects of the present invention are as follows: the antitumor compound provided by the present invention has one or more of the following effects, including: 1) having in vitro inhibitory activity against tumor cell proliferation; 2) having plasma stability; 3) having antitransporter transport capability; 4) having in vivo tumor-suppressing effect; 5) having a bystander effect; and 6) having good in vivo safety. Detailed Implementation

[0113] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention.

[0114] The following are some of the synthesis methods of intermediates used in the embodiments of this application:

[0115] Intermediate Int-1 and its synthesis method

[0116] first step

[0117] A mixture of Int-1-1 (6.3 g, 23.6 mmol), CD3I (17.1 g, 117.6 mmol), Pd(amphos)Cl2 (418 mg, 0.588 mmol), and CsF (12.6 g, 82.77 mmol) in DMF (80 mL) and water (16 mL) was degassed with nitrogen and stirred at 45 °C for 18 hours. The mixture was cooled, 100 mL of water was added, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain intermediate Int-1-2.

[0118] 1 HNMR (400MHz, CDCl3) δ8.00–7.92(m,1H),7.89(dd,J=9.3,2.3Hz,1H),7.41–7.31(m,1H).

[0119] Step 2

[0120] Intermediate Int-1-2 (3.0 g, 18.97 mmol) was stirred at 60 °C with concentrated H₂SO₄ (15 mL) and heptane (15 mL). Then, NBS (4.05 g, 22.76 mmol) was carefully added at 60 °C, and the mixture was stirred at 60 °C for 1 hour. The mixture was cooled to room temperature. The mixture was poured into cold water (100 mL). The mixture was extracted with EtOAc (150 mL x 3). The organic layer was washed with 6.5% (wt%) NaHCO₃ solution (100 mL) and 5% (wt%) Na₂SO₃ solution. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain crude intermediate Int-1-3.

[0121] Step 3

[0122] A mixture of intermediate Int-1-3 (3.6 g, 15.26 mmol), iron powder (4.3 g, 76.3 mmol), and NH4Cl (4.0 g, 76.3 mmol) in ethanol (60 mL) and water (12 mL) was stirred at 75 °C for 2 hours. The mixture was filtered, and the filter cake was washed with ethanol (100 mL x 2). The filtrate was concentrated. The residue was dissolved in EtOAc (200 mL x 3). The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain intermediate Int-1-4.

[0123] MS m / z(ESI): 209.0 [M+1]

[0124] Step 4

[0125] At room temperature, Ac₂O (1.66 g, 16.32 mmol) was added to a mixture of intermediate Int-1-4 (2.8 g, 13.6 mmol) and Et₃N (4.1 g, 40.8 mmol) in EtOAc (120 mL), and the mixture was stirred at room temperature for 18 hours. The mixture was quenched with water. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain intermediate Int-1-5.

[0126] 1 HNMR (400MHz, DMSO-d6) δ10.17(s,1H),7.66(s,1H),7.47(dd,J=11.8,1.7Hz,1H),2.04(d,J=6.3Hz,3H).

[0127] Step 5

[0128] A mixture of intermediate Int-1-5 (1.2 g, 4.84 mmol), butyric acid (497 mg, 5.77 mmol), Pd(OAc)2 (36 mg, 0.161 mmol), tris(o-tolyl)phosphine (98 mg, 0.322 mmol), and DIPEA (1.4 g, 10.8 mmol) in THF (36 mL) and water (9 mL) was degassed with nitrogen and stirred at 75 °C for 18 hours. The mixture was filtered, and the pH of the filtrate was adjusted to 4–5 with 5N HCl solution. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain intermediate Int-1-6.

[0129] MS m / z(ESI): 255.1 [M+1]

[0130] Step 6

[0131] A mixture of intermediate Int-1-6 (1.3 g, 5.11 mmol) and Pd / C (700 mg) in 2-methyltetrahydrofuran (200 mL) was stirred at 40 °C under hydrogen (14.7 psi) for 2 hours. The suspension mixture was filtered, and the filter cake was washed with THF and MeOH. The combined filtrates were concentrated to obtain intermediate Int-1-7.

[0132] 1 HNMR(400MHz,DMSO-d6)δ12.07(s,1H),9.99(s,1H),7.42(dd,J=12.3,2.0Hz,1H),7.05(d ,J=1.2Hz,1H),2.60–2.53(m,2H),2.28(t,J=7.2Hz,2H),2.02(s,3H),1.77–1.66(m,2H).

[0133] Step 7

[0134] TFAA (4.0 mL) was added to a mixture of intermediate Int-1-7 (1.3 g, 5.07 mmol) and TFA (12 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into an aqueous solution of 50% CH3CN (200 mL). The pH of the mixture was adjusted to 7 with 25% (wt%) NaOH solution. Approximately 100 mL of water was added, and the mixture was stirred at room temperature for 30 min to obtain a white suspension. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain intermediate Int-1-8.

[0135] 1 HNMR (400MHz, DMSO-d6) δ12.18(s,1H),8.29(d,J=13.2Hz,1H),2.89(t,J=6.1Hz,2H),2.70–2.59(m,2H),2.15(s,3H),2.04–1.93(m,2H).

[0136] Step 8

[0137] At 0°C, a solution of intermediate Int-1-8 (900 mg, 3.78 mmol) in tetrahydrofuran (5 mL) was added dropwise to a mixture of KOtBu (1.48 g, 13.22 mmol) and THF (100 mL), and the mixture was stirred at 0°C for 30 minutes. Then, a solution of n-butyl nitrite (778 mg, 7.55 mmol) in THF (5 mL) was added dropwise at 0°C. The resulting mixture of intermediate Int-1-9 was ready for use in the next step without further purification.

[0138] MS m / z(ESI): 269.1 [M+1]

[0139] Step 9

[0140] To a mixture of intermediate Int-1-9 (1.0 g, 3.74 mmol) and THF (100 mL), AcOH (4.2 mL), Ac₂O (4.2 mL), and Pt / C (550 mg) were added. The mixture was stirred under hydrogen (15 psi) for 2 hours. The suspension mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate Int-1-10.

[0141] 1 HNMR (400MHz, DMSO-d6) δ11.88(s,1H),8.29(d,J=13.1Hz,1H),8.20(d,J=7.8Hz,1H),4.6 2(ddd,J=12.9,7.9,4.9Hz,1H),3.11–2.93(m,2H),2.22–2.15(m,4H),2.04–1.90(m,4H).

[0142] Step 10

[0143] At room temperature, a MeOH solution of HCl (4.0 M, 60 mL, 240 mmol) was added to a MeOH solution of intermediate Int-1-10 (700 mg, 2.372 mmol) in 60 mL, and the mixture was stirred for 18 hours at room temperature. The solvent was removed, and the residue was dissolved in DCM (200 mL) and washed with saturated NaHCO3 solution. The organic layer was concentrated and purified by silica gel column chromatography to obtain intermediate Int-1-11. MS m / z (ESI): 254.2 [M+1]

[0144] Step 11

[0145] A mixture of intermediate Int-1-11 (530 mg, 2.09 mmol), (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]-indene-3,6,10(4H)-trione (670 mg, 2.55 mmol), and PPTS (340 mg, 1.35 mmol) in toluene (20 mL) was sealed and sealed for 36 hours. The solvent was removed, and intermediate Int-1-12 was obtained by column chromatography in DCM [(10% MeOH in DCM) in DCM = 0% to 62%]

[0146] MS m / z(ESI): 481.3 [M+1]

[0147] Step Twelve

[0148] The intermediate Int-1-12 (50 mg, 0.104 mmol) was stirred in a mixture of 8N HCl (4 mL), AcOH (1 mL), and toluene (2 mL) at 100 °C for 8 hours. The mixture was cooled and filtered through diatomaceous earth. The filter cake was washed with a solution of MeOH and water (1:1, 30 mL). The combined filtrates were concentrated to give the crude intermediate Int-1-13.

[0149] MS m / z(ESI):439.1[M+1].

[0150] Step Thirteen

[0151] Intermediate Int-1-13 (100 mg crude product) was purified by high performance liquid chromatography [MeCN in (0.1% TFA in H2O) = 20% to 50%], yielding intermediates Int-1 and Int-1.

[0152] Int-1:

[0153] 1HNMR(400MHz, DMSO-d6)δ8.47(s,3H),7.89(d,J=10.9Hz,1H),7.35(s,1H),6.55(s,1H),5.72(d,J=19.2Hz,1H),5.51–5.35(m,3H),5.11(s,1H), 3.28(d,J=4.9Hz,1H),3.11(t,J=13.1Hz,1H),2.55(d,J=6.4Hz,1H),2.2 0(t,J=13.9Hz,1H),1.88(tt,J=14.1,7.2Hz,2H),0.88(t,J=7.3Hz,3H).

[0154] Int-1':

[0155] 1HNMR (400MHz, DMSO-d6) δ8.43(s,3H),7.90(d,J=10.8Hz,1H),7.36(s,1H),6.54(s,1H),5.71(d,J=19.3Hz,1H),5.52–5.36(m,3H),5.11( s,1H),3.30–3.26(m,1H),3.10(t,J=13.4Hz,1H),2.54(t,J=5.6Hz,1H),2.21(d,J=12.9Hz,1H),1.95–1.80(m,2H),0.88(t,J=7.3Hz,3H).

[0156] Intermediate Int-2 and its synthesis method

[0157] first step

[0158] A mixture of Int-2-1 (30 g, 157.8 mmol) and NCS (25.3 g, 189.4 mmol) in N,N-dimethylformamide (300 mL) was stirred at 30 °C for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, and ice water was added. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water and brine and dried over Na₂SO₄. The mixture was concentrated and purified by silica gel chromatography to obtain intermediate Int-2-2.

[0159] MS m / z(ESI): 223.9 [M+1]

[0160] Step 2

[0161] Acetyl chloride (6.29 g, 80.2 mmol) was added dropwise to a mixture of intermediate Int-2-2 (9 g, 40.1 mmol) and triethylamine (12.17 g, 120.3 mmol) in dichloromethane (150 mL) at 0 °C. The mixture was stirred for 1 hour. The mixture was washed with water and brine, dried over Na₂SO₄, concentrated, and purified by silica gel chromatography to obtain intermediate Int-2-3.

[0162] MS m / z(ESI): 266.1 [M+1]

[0163] Step 3

[0164] Under nitrogen protection, a mixture of intermediate Int-2-3 (8.4 g, 31.52 mmol), butyric acid (3.26 g, 37.82 mmol), tri-o-tolylphosphine (1.92 g, 6.3 mmol), palladium acetate (707 mg, 3.15 mmol), and N,N-diisopropylethylamine (12.22 g, 94.56 mmol) in dioxane / water (100 mL / 50 mL) was stirred at 100 °C for 16 hours. After cooling to room temperature, an aqueous solution of sodium hydroxide (approximately 60 mL, 1 M) was added, and the mixture was washed with ethyl acetate. The pH of the aqueous layer was adjusted to 3–4 with concentrated hydrochloric acid. Extraction was performed with ethyl acetate. The combined organic layers were washed with brine and dried over Na₂SO₄. The crude intermediate Int-2-4 was obtained by concentration.

[0165] MS m / z(ESI): 272.0 [M+1]

[0166] Step 4

[0167] The mixture of intermediate Int-2-4 (8.54 g, 31.44 mmol) and palladium on carbon (1 g, 10% w / w) in tetrahydrofuran (100 mL) was stirred for 2 hours at room temperature under hydrogen atmosphere. The solid was filtered off. The organic phase was concentrated to give crude intermediate Int-2-5.

[0168] MS m / z(ESI): 274.0 [M+1]

[0169] Step 5

[0170] At 0 °C, trifluoroacetic anhydride (26.32 g, 125.3 mmol) was added to a mixture of intermediate Int-2-5 (6.86 g, 25.06 mmol) and trifluoroacetic acid (28.57 g, 250.6 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, concentrated, and purified by silica gel chromatography to obtain crude intermediate Int-2-6.

[0171] MS m / z(ESI): 256.0 [M+1]

[0172] Step 6

[0173] Under nitrogen protection, at 0°C, a solution of intermediate Int-2-6 (700 mg, 2.74 mmol) in tetrahydrofuran (10 mL) was added dropwise to a mixture of potassium tert-butoxide (675 mg, 6.02 mmol) in tetrahydrofuran and tert-butanol (20 mL / 2 mL), and the mixture was stirred at 0°C for 30 minutes. Then, tert-butyl nitrite (451 mg, 4.38 mmol) was added dropwise to the above reaction solution at 0°C, and stirring was continued for 2 hours. The solution was diluted with saturated ammonium chloride aqueous solution at 0°C, extracted with ethyl acetate, washed with brine, and dried over Na₂SO₄. The concentrate was then used to obtain crude intermediate Int-2-7.

[0174] MS m / z(ESI): 285.0 [M+1]

[0175] Step 7

[0176] A mixture of intermediate Int-2-7 (150 mg, 0.53 mmol), (9H-fluorene-9-yl)methyl(2,5-dioxopyrrolidone-1-yl) carbonate (197 mg, 0.58 mmol), and palladium on carbon (15 mg, 10% w / w) in tetrahydrofuran and methanol (20 mL / 10 mL) was stirred for 2 hours at room temperature under hydrogen atmosphere. The solid was filtered off, concentrated, and purified by silica gel chromatography to obtain intermediate Int-2-8.

[0177] MS m / z(ESI): 493.1 [M+1]

[0178] Step 8

[0179] At room temperature, a MeOH solution of HCl (4.0 M, 20 mL, 80 mmol) was added to a MeOH solution of intermediate Int-2-8 (200 mg, 0.406 mmol) in 20 mL, and the mixture was stirred at room temperature for 18 hours. The solvent was removed, the residue was dissolved in DCM, and washed with saturated NaHCO3 solution. The organic layer was concentrated to obtain crude intermediate Int-2-9.

[0180] Step 9

[0181] Under nitrogen protection, a mixture of intermediate Int-2-9 (50 mg, 0.11 mmol), (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f] N-3,6,10(4H)-trione (44 mg, 0.17 mmol), and pyridine p-toluenesulfonate (27 mg, 0.11 mmol) in toluene (2 mL) was stirred at 120 °C for 16 hours. The mixture was concentrated and purified by silica gel chromatography to obtain intermediate Int-2-10.

[0182] MS m / z (ESI): 678.2 [M+1]

[0183] Step 10

[0184] The intermediate Int-2-10 (30 mg, 0.044 mmol) and diethylamine (6 mg, 0.088 mmol) were stirred in N,N-dimethylformamide (1 mL) at room temperature for 16 hours. The mixture was purified by high-performance liquid chromatography (column: Wepure Prep C18 10 μm 21.2*250 mm, Mobile Phase: A: water (0.1% TFA) B: acetonitrile; 5-40% B in 8 min, stop at 16 min), and lyophilized to obtain intermediates Int-2 and Int-2'.

[0185] Int-2:MS m / z(ESI):456.0[M+1]

[0186] Int-2':MS m / z(ESI):456.0[M+1]

[0187] Intermediate Int-3 and its synthesis method

[0188] first step

[0189] Concentrated sulfuric acid (10.0 g, 98% aqueous solution) was added to a solution of Int-3-1 (2.50 g, 10.6 mmol) in glacial acetic acid (7.5 mL) at 0 °C, followed by dropwise addition of an aqueous solution of sodium nitrite (1.47 g, 21.2 mmol) (3 mL) below 10 °C. The mixture was stirred at 0 °C for 1 hour. LCMS analysis showed that the reaction mixture was directly added dropwise to an aqueous solution of potassium iodide (3.52 g, 21.2 mmol) (5 mL) below 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was dissolved in ice water, extracted with ethyl acetate, and the combined organic layers were washed with water, a saturated aqueous solution of sodium thiosulfate, and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by normal-phase silica gel column chromatography yielded intermediate Int-3-2.

[0190] 1 HNMR (400MHz, CDCl3) δ8.39 (s, 1H), 7.84 (dd, J = 10.4, 1.2Hz, 1H).

[0191] Step 2

[0192] Under argon protection, a mixture of intermediate Int-3-2 (3.46 g, 10.0 mmol), cuprous iodide (5.73 g, 30.0 mmol), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (7.68 g, 40.0 mmol) in N,N-dimethylformamide (35 mL) was heated to 75 °C and stirred for 18 hours. The mixture was cooled and dissolved in ethyl acetate, washed with water and brine, dried, and concentrated. Purification was performed using a normal-phase silica gel column chromatography to obtain intermediate Int-3-3.

[0193] 1 HNMR (400MHz, CDCl3) δ8.32 (dd, J=2.4, 1.6Hz, 1H), 7.84 (dd, J=7.2, 2.8Hz, 1H).

[0194] Step 3

[0195] Under nitrogen protection, a mixture of intermediate Int-3-3 (610 mg, 2.1 mmol), iron powder (235 mg, 4.2 mmol), ammonium chloride (225 mg, 4.2 mmol), and ethanol (7.5 mL) and water (2.5 mL) was stirred in an oil bath at 80 °C for 2 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain intermediate Int-3-4.

[0196] MS m / z(ESI): 258.0 [M+1]

[0197] Step 4

[0198] Intermediate Int-3-4, acetic anhydride (260 mg, 2.52 mmol), and 4-dimethylaminopyridine (45 mg, 0.37 mmol) were mixed in toluene (10 mL) and stirred at 110 °C for 3 hours. The mixture was cooled to 30 °C, mixed with a small sample, and concentrated to dryness. The residue was purified by normal-phase silica gel column chromatography to obtain intermediate Int-3-5.

[0199] MS m / z(ESI): 300.0 [M+1]

[0200] Step 5

[0201] Intermediate Int-3-5 (3.0 g, 10.0 mmol), butyric acid (2.1 g, 24.0 mmol), palladium acetate (225 mg, 1.0 mmol), tri-o-tolylphosphine (610 mg, 2.0 mmol), and diisopropylethylamine (4.2 g, 40.0 mmol) were stirred in an oil bath at 100 °C under argon protection for 18 hours. The reaction mixture was diluted with water, the pH was adjusted to 5 with concentrated hydrochloric acid, and the solution was extracted with ethyl acetate. The combined organic phases were dried, concentrated, and the crude product was purified by normal-phase silica gel column chromatography to obtain intermediate Int-3-6.

[0202] MS m / z(ESI): 306.1 [M+1]

[0203] Step 6

[0204] The intermediate Int-3-6 (1.2 g, 3.9 mmol), palladium on carbon (400 mg, catalyst), and a mixture of tetrahydrofuran (25 mL) were stirred in hydrogen at 20 °C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by normal-phase silica gel column chromatography to obtain intermediate Int-3-7.

[0205] MS m / z(ESI): 308.1 [M+1]

[0206] Step 7

[0207] Under argon atmosphere, a mixture of intermediate Int-3-7 (1.0 g, 3.26 mmol) and trifluoroacetic anhydride (2.5 mL) in trifluoroacetic acid (2.5 mL) was stirred at 50 °C for 2 hours. The solution was combined with the small-scale reaction solution and concentrated. The mixture was purified by normal-phase silica gel column chromatography to obtain intermediate Int-3-8.

[0208] MS m / z(ESI): 290.0 [M+1]

[0209] Step 8

[0210] Under argon protection and with the temperature controlled at 0°C in an ice bath, a dry tetrahydrofuran solution (5 mL) of intermediate Int-3-8 (560 mg, 1.9 mmol) was added to a mixture of potassium tert-butoxide (760 mg, 6.8 mmol) and tetrahydrofuran (13 mL). The mixture was stirred for 0.5 hours, followed by the addition of a tetrahydrofuran solution of tert-butyl nitrite (390 mg, 3.8 mmol). The mixture was then stirred for 3 hours at 0–20°C. The reaction was quenched with a saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, washed with brine, dried, and concentrated. The crude intermediate Int-3-9 was purified by normal-phase silica gel column chromatography.

[0211] Step 9

[0212] FmocOSu (150 mg, 0.45 mmol) and palladium on carbon (40 mg, catalyst) were added to a methanol / tetrahydrofuran (3+3 mL) solution of intermediate Int-3-9 (130 mg, 0.41 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 hour under hydrogen protection. The mixture was then filtered. The filtrate was concentrated, and the crude product was purified by normal-phase silica gel column chromatography to obtain intermediate Int-3-10.

[0213] MS m / z(ESI): 527.2 [M+1]

[0214] Step 10

[0215] At room temperature, a MeOH solution of HCl (4.0 M, 20 mL, 80 mmol) was added to a MeOH solution of intermediate Int-3-10 (200 mg, 0.380 mmol) in 20 mL, and the mixture was stirred at room temperature for 18 hours. The solvent was removed, the residue was dissolved in DCM, and washed with saturated NaHCO3 solution. The organic layer was concentrated to obtain crude intermediate Int-3-11.

[0216] Step 11

[0217] Under nitrogen protection, a mixture of intermediate Int-3-11 (180 mg, 0.37 mmol), (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f] indene-3,6,10(4H)-trione (120 mg, 0.46 mmol), and p-toluenesulfonic acid pyridinium salt (60 mg, 0.24 mmol) in toluene (5 mL) was stirred at 120 °C for 16 hours. The mixture was concentrated, and the crude product was purified by normal-phase silica gel column chromatography to obtain intermediate Int-3-12. MS m / z (ESI): 712.1 [M+1]

[0218] Step Twelve

[0219] Diethylamine (18 mg, 0.25 mmol) was added to a solution of intermediate Int-3-12 (87 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL) at 0 °C. The mixture was then stirred at 20 °C for 18 hours under nitrogen protection. The reaction mixture was analyzed by LCMS. Intermediates Int-3 and Int-3' were then prepared by high performance liquid chromatography (mobile phase: A: water (0.1% trifluoroacetic acid) B: acetonitrile; elution gradient: 13-43% B for 8 min, stop for 16 min; column: Wepure Prep C18 10 μm 21.2*250 mm).

[0220] Int-3:

[0221] MS m / z(ESI): 490.1 [M+1]

[0222] Int-3':

[0223] MS m / z(ESI): 490.1 [M+1]

[0224] Intermediate Int-4 and its synthesis method

[0225] first step

[0226] Int-4-1 (100 mg, 0.23 mmol) was dissolved in DCM (2 mL), and DIEA (89 mg, 0.69 mmol) and oxaloyl chloride monomethyl ester (84 mg, 0.69 mmol) were added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with NaHCO3, extracted with DCM, and the organic layer was washed with water and brine. The mixture was dried with anhydrous Na2SO4, filtered, and concentrated to obtain the crude intermediate Int-4-2.

[0227] MS m / z(ESI): 522.2 [M+1]

[0228] Step 2

[0229] Intermediate Int-4-2 (90 mg, 0.17 mmol) was dissolved in methanol (2 mL) and water (1 mL), and LiOH (20.4 mg, 0.85 mmol) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the methanol was removed by rotary evaporation under reduced pressure, and the pH was adjusted to 4-5 with 2 M dilute hydrochloric acid. The intermediate Int-4 was obtained by purification by C18 reverse column chromatography.

[0230] MS m / z (ESI): 508.2 [M+1]

[0231] Example 1: Synthesis of CP2031

[0232] first step

[0233] Under a nitrogen atmosphere, CP2031-1 (5 g, 48.07 mmol, 1 eq) and potassium carbonate (9.95 g, 72.11 mmol, 1.5 eq) were dispersed in 80 mL of DMF solution. Benzyl bromide (9.85 g, 57.6 mmol, 1.2 eq) was added dropwise under ice-water bath cooling. The reaction was then heated to room temperature and stirred for 16 h. After the reaction was complete, the reaction mixture was poured into crushed ice (approximately 200 g) and stirred to quench the reaction. The resulting slurry was extracted with ethyl acetate, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain intermediate CP2031-2.

[0234] MS m / z(ESI): 195.1 [M+1]

[0235] Step 2

[0236] Intermediate CP2031-2 (3.8 g, 19.58 mmol, 1 eq) was dissolved in 120 mL of dichloromethane. Under ice bath conditions, Dys-Martin reagent (16.6 g, 39.2 mmol, 2 eq) was added in portions. The reaction mixture was brought to room temperature and stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution. The reaction mixture was filtered and separated into layers. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain intermediate CP2031-3.

[0237] MS m / z(ESI): 215.1 [M+1]

[0238] Step 3

[0239] Intermediate CP2031-3 (1.2 g, 6.25 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), and ammonium chloride aqueous solution (331 mg dissolved in 5 mL water, 6.25 mmol, 1 eq) was added. Sodium cyanide (0.61 g, 12.5 mmol, 2 eq) was added with stirring, and the reaction was continued with stirring at room temperature for 6 hours. The reaction solution was diluted with water, and the organic phase was washed successively with water and saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain intermediate CP2031-4.

[0240] MS m / z(ESI): 220.1 [M+1]

[0241] Step 4

[0242] Intermediate CP2031-4 (760 mg, 3.47 mmol, 1 eq) and hydrogen chloride solution in methanol (4 M, 20 mL) were added to a sealed tube equipped with a stir bar. The tube was sealed and stirred at 80 °C for 36 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain intermediate CP2031-5.

[0243] MS m / z(ESI): 253.1 [M+1]

[0244] Step 5

[0245] Intermediate CP2031-5 (360 mg, 1.43 mmol, 1 eq) was dissolved in dichloromethane (10 mL), followed by the addition of Dys-Martin reagent (606 mg, 1.43 mmol, 1 eq), and the reaction was stirred at this temperature. The reaction solution was then concentrated and purified by silica gel column chromatography to obtain intermediate CP2031-6.

[0246] MS m / z(ESI): 251.1 [M+1]

[0247] Step 6

[0248] To a methanol (3 mL) solution of intermediate CP2031-5 (140 mg, 0.56 mmol, 1 eq) , 1 mL of an aqueous solution of lithium hydroxide (67 mg, 2.8 mmol, 5 eq) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove methanol, and the pH of the residue was adjusted to 5. The residue was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to dryness to obtain intermediate CP2031-6.

[0249] MS m / z(ESI): 237.1 [M+1]

[0250] Step 7

[0251] Intermediate CP2031-7 (85 mg, 0.22 mmol, 1 eq), ethatecan mesylate (117 mg, 0.22 mmol, 1 eq), HATU (108 mg, 0.286 mmol, 1.3 eq), N,N-dimethylformamide (1 mL), and diisopropylethylamine (113 mg, 0.88 mmol, 4 eq) were stirred at room temperature for 1 hour. After the reaction was complete, intermediate CP2031-8 was obtained by preparative high-performance liquid chromatography.

[0252] MS m / z (ESI): 654.4 [M+1]

[0253] Step 8

[0254] Intermediate CP2031-8 (25 mg, 0.038 mmol, 1 eq) was dissolved in methanol (2 mL), and palladium on carbon (30 mg) was added. The mixture was stirred under a hydrogen balloon atmosphere for 1 hour at room temperature. The reaction solution was filtered, and the filtrate was concentrated. The product CP2031 was purified by reversed-phase chromatography.

[0255] 1 H NMR(400MHz,DMSO)δ9.20(d,J=8.8Hz,1H),7.79(d,J=10.9Hz,1H),7.31(s,1 H),6.53(s,1H),5.58(dd,J=14.1,6.2Hz,1H),5.42(s,2H),5.28–5.12(m,2H ),4.96(t,J=4.9Hz,1H),3.74(d,J=4.7Hz,2H),3.29–3.06(m,2H),2.39(s,3 H),2.24-2.16(m,2H),1.93-1.80(m,2H),1.20(s,6H),0.87(t,J=7.3Hz,3H).

[0256] Example 2: Synthesis of CP2032

[0257] first step

[0258] CP2032-1 (1g, 9.8mmol, 1eq) was dissolved in DMF (10mL), and NaH (470mg, 11.8mmol, 1.2eq) was added at 0℃. After stirring for half an hour, BnBr (1.67g, 9.8mmol, 1eq) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic layer was washed with water and brine. The mixture was dried with anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The intermediate CP2032-2 was obtained by column chromatography.

[0259] MS m / z(ESI): 215.4 [M+23]

[0260] Step 2

[0261] Intermediate CP2032-2 (800 mg, 4.17 mmol) was dissolved in DCM, and Dess-Martin (2.65 g, 6.25 mmol) was added at 0 °C. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, the mixture was quenched with water, extracted with DCM, and the organic layer was washed with water and brine. The mixture was dried with anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. Intermediate CP2032-3 was obtained by column chromatography.

[0262] MS m / z(ESI): 213.3 [M+23]

[0263] Step 3

[0264] Intermediate CP2032-3 (550 mg, 2.89 mmol) was dissolved in THF and water, NH4Cl (170 mg, 3.18 mmol) was added, and after stirring for half an hour, NaCN (156 mg, 3.18 mmol) was added. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic layer was washed with water and brine. The mixture was dried with anhydrous Na2SO4, filtered, and concentrated to obtain crude intermediate CP2032-4.

[0265] MS m / z(ESI): 240.4 [M+23]

[0266] Step 4

[0267] Intermediate CP2032-4 (350 mg, 1.61 mmol) was dissolved in HCl-MeOH solution and reacted at 80 °C for 12 hours. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure, extracted with water and ethyl acetate, and the organic layer was washed with water and brine. The solution was dried with anhydrous Na2SO4, filtered and concentrated to obtain the crude product. Intermediate CP2032-5 was obtained by column chromatography.

[0268] MS m / z(ESI): 273.3 [M+23]

[0269] Step 5

[0270] Intermediate CP2032-5 (200 mg, 0.8 mmol) was dissolved in DCM, and Dess-Martin (509 mg, 1.2 mmol) was added at 0 °C. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, the mixture was quenched with water, extracted with DCM, and the organic layer was washed with water and brine. The mixture was dried with anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. Intermediate CP2032-6 was obtained by column chromatography.

[0271] MS m / z(ESI): 249.1 [M+1]

[0272] Step 6

[0273] Intermediate CP2032-6 (100 mg, 0.4 mmol) was dissolved in methanol (2 mL) and water (1 mL), and LiOH (28.8 mg, 1.2 mmol) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the methanol was removed by concentration under reduced pressure. The pH was adjusted to 4-5 with 2 M dilute hydrochloric acid. The intermediate CP2032-7 was obtained by purification by C18 reverse column chromatography.

[0274] MS m / z(ESI): 257.1 [M+23]

[0275] Step 7

[0276] Intermediate CP2032-6 (20 mg, 0.08 mmol), ethatecan mesylate (33.8 mg), and HATU (35 mg) were dissolved in DMF (1 mL), and DIEA (20 mg, 0.16 mmol) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was purified by C18 reverse column chromatography to obtain intermediate CP2032-8.

[0277] MS m / z (ESI): 652.3 [M+1]

[0278] Step 8

[0279] The intermediate CP2032-8 (15 mg) was dissolved in methanol (1 mL), Pd / C (2 mg) was added, and the mixture was replaced three times with H2 spheres. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the product CP2032 was obtained by purification by C18 reverse column.

[0280] 1H NMR(400MHz, CDCl3) δ9.29(d,J=8.7Hz,1H),7.81(d,J=11.0Hz,1H),7.32(s,1H) ,6.53(s,1H),5.65–5.52(m,1H),5.43(s,2H),5.34–5.12(m,2H),4.80(t,J=5.5H z,1H),3.73(d,J=5.5Hz,2H),3.25-3.14(m,2H),2.40(s,3H),2.27–2.15(m,2H) ,1.91-1.83(m,2H),1.40–1.29(m,2H),1.12–1.03(m,2H),0.88(t,J=7.3Hz,3H).

[0281] Example 3: Synthesis of CP3075

[0282] first step

[0283] To a solution of intermediate Int-1 (20 mg, 0.046 mmol) in dichloromethane (2 mL), N,N-diisopropylethylamine (30 mg, 0.230 mmol) and methyl 2-chloro-2-oxoacetate (17 mg, 0.138 mmol) were added. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Wepure prep C18 10 μm 21.2*250 mm; mobile phase: A: water (0.1% TFA) B: acetonitrile; gradient: 20-50% B over 8 minutes, stopped after 16 minutes; flow rate: 30 mL / min), yielding intermediate CP3075-1.

[0284] MS m / z (ESI): 525.2 [M+1]

[0285] Step 2

[0286] To a tetrahydrofuran (1 mL) solution of intermediate CP3075-1 (18 mg, 0.034 mmol), 0.02 mL of a 10% lithium hydroxide aqueous solution was added. The resulting solution was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (10 mL). The solution was then acidified with hydrochloric acid to pH 3-4, and the mixture was freeze-dried to obtain intermediate CP3075-2.

[0287] MS m / z(ESI): 511.3 [M+1]

[0288] Step 3

[0289] To a solution of intermediate CP3075-2 (15 mg, 0.029 mmol) in N,N-dimethylformamide (1 mL), 2-(methylamino)ethanol-1-ol (3 mg, 0.035 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (13 mg, 0.035 mmol), and N,N-diisopropylethylamine (11 mg, 0.087 mmol) were added. The resulting solution was stirred at room temperature for 3 hours. The reactants were purified by preparative high-performance liquid chromatography (HPLC) (column: Boston prep C18 10 μm 21.2 × 250 mm; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; gradient: slope of 12-42% within 8 minutes, stopped after 16 minutes; flow rate: 30 mL / min), yielding product CP3075.

[0290] 1 H NMR (400MHz, DMSO-d6) δ9.31(dd,J=21.0,8.6Hz,1H),7.81(dd,J=10.9,3.2Hz,1H),7.31(s,1H),6.53(s,1H),5.61(s,1H),5.42(s,2H),5.35-5.16( m,2H),3.52(dd,J=20.3,14.4Hz,4H),3.23-3.14(m,2H),3.00(d,J=84.7H z,3H),2.21(s,2H),1.93-1.80(m,2H),1.23(s,1H),0.87(t,J=7.3Hz,3H).

[0291] Example 4: Synthesis of CP2027

[0292] first step

[0293] Intermediate Int-4 (40 mg, 0.08 mmol), N-[2-(tert-butyldimethylsiloxy)ethyl]methylamine (17 mg), and HATU (36 mg) were dissolved in DMF (1 mL), and DIEA (19 mg, 0.16 mmol) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was purified by C18 reverse column chromatography to obtain intermediate CP2027-2.

[0294] MS m / z (ESI): 679.4 [M+1]

[0295] Step 2

[0296] Intermediate CP2027-2 (20 mg) was dissolved in DCM (1 mL), and TFA (0.3 mL) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was evaporated under reduced pressure and purified by C18 reverse column chromatography to obtain product CP2027.

[0297] 1 H NMR (400MHz, DMSO) δ9.30 (dd, J=20.8, 8.7Hz, 1H), 7.81 (dd, J=11.0, 3.4Hz, 1H), 7.3 1(s,1H),6.53(s,1H),5.62-5.58(m,1H),5.42(s,2H),5.34–5.18(m,2H),4.80(s,1 H),3.56-3.51(m,2H),3.21–3.16(m,1H),3.10(s,1H),2.96–2.88(m,2H),2.35(s,3 H),2.32-2.15(m,2H),1.92-1.81(m,2H),1.23-1.14(m,2H),0.87(t,J=7.3Hz,3H).

[0298] Example 5: Synthesis of CP2030

[0299] Intermediate Int-4 (20 mg), 2-(ethylamino)ethanol (3.6 mg), and HATU (18 mg) were dissolved in DMF (1 mL), and DIEA (10.2 mg) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the product CP2030 was obtained by purification using a C18 reverse column.

[0300] 1 H NMR (400MHz, DMSO-d6) δ9.36-9.28 (m, 1H), 7.81 (dd, J = 10.9, 2.4Hz, 1H), 7. 31(s,1H),6.53(s,1H),5.72-5.53(m,1H),5.42(s,2H),5.35-5.22(m,2H), 4.80-4.72(m,1H),3.59-3.36(m,6H),3.24-3.13(m,2H),2.40(s,4H),2.28 -2.11(m,2H),1.90-1.84(m,2H),1.17-1.05(m,3H),0.87(t,J=7.2Hz,3H).

[0301] Example 6: Synthesis of CP2029

[0302] Intermediate Int-4 (20 mg), 3-amino-1-propanol (3.6 mg), and HATU (18 mg) were dissolved in DMF (1 mL), and DIEA (10.2 mg) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the product CP2029 was obtained by purification using a C18 reverse column.

[0303] 1 H NMR (400MHz, DMSO-d6) δ9.49(d,J=9.0Hz,1H),8.91(t,J=6.0Hz,1H),7.79(d,J=10.9Hz,1H),7.30(s,1H),6.52(s,1H),5.54(d,J=5.3Hz,1H),5.40(s ,2H),5.13(s,2H),3.46-3.29(m,2H),3.27-3.06(m,4H),2.39(s,3H),2.35 -2.16(m,3H),1.89-1.83(m,2H),1.71-1.60(m,2H),0.87(t,J=7.3Hz,3H).

[0304] Example 7: Synthesis of CP2028

[0305] first step

[0306] Intermediate Int-4 (40 mg, 0.08 mmol), 2-((tert-butyldimethoxy)ethylamine (16.6 mg), and HATU (36 mg) were dissolved in DMF (1 mL), and DIEA (19 mg, 0.16 mmol) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was purified by C18 reverse column chromatography to obtain intermediate CP2028-2.

[0307] MS m / z (ESI): 665.3 [M+1]

[0308] Step 2

[0309] Intermediate CP2028-2 (20 mg) was dissolved in DCM (1 mL), and TFA (0.3 mL) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was evaporated under reduced pressure and purified by C18 reverse column chromatography to obtain product CP2028.

[0310] 1H NMR (400MHz, DMSO) δ9.51 (d, J = 9.0 Hz, 1H), 8.77 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 10. 9Hz,1H),7.31(s,1H),6.52(s,1H),5.54(dd,J=13.3,8.0Hz,1H),5.40(s,2H),5 .14(s,2H),4.78(t,J=5.7Hz,1H),3.51-3.46(m,2H),3.28-3.13(m,2H),2.39(s ,3H),2.25-2.20(m,2H),2.01-1.81(m,2H),1.23(s,2H),0.86(t,J=4.0Hz,3H).

[0311] Example 8: Synthesis of CP3093

[0312] first step

[0313] At 0 °C, triethylamine (17 mg, 0.17 mmol) and HATU (22 mg, 0.057 mmol) were added to a solution of intermediate Int-1 (25 mg, 0.057 mmol) and intermediate CP2032-7 (15 mg, 0.063 mmol) in N,N-dimethylformamide (1 mL). The resulting solution was stirred at room temperature until the reaction was complete. The resulting mixture was purified by high performance liquid chromatography to obtain intermediate CP3093-2.

[0314] MS m / z (ESI): 655.3 [M+1]

[0315] Step 2

[0316] To a methanol / tetrahydrofuran mixture (2 mL / 2 mL) of intermediate CP3093-2 (12 mg, 0.018 mmol), wet palladium on carbon (15 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere until the reaction was complete. The reaction mixture was filtered and purified by preparative high-performance liquid chromatography to obtain product CP3093.

[0317] 1H NMR(400MHz,DMSO)δ9.30(d,J=8.8Hz,1H),7.80(d,J=11.0Hz,1H),7.31(s,1H ),6.54(s1H),5.59(s,1H),5.42(s,2H),5.31–5.17(m,2H),4.80(t,J=5.5Hz, 1H),3.72(d,J=5.4Hz,2H),3.17(s,2H),2.20(s,2H),1.93–1.79(m,2H),1.32 (t,J=10.1Hz,2H),1.23(s,1H),1.07(d,J=2.4Hz,2H),0.87(t,J=7.3Hz,3H).

[0318] Example 9: Synthesis of CP3094

[0319] first step

[0320] Int-1 (100 mg, 0.23 mmol) was dissolved in DCM (2 mL), and DIEA (89 mg, 0.69 mmol) and oxaloyl chloride monomethyl ester (84 mg, 0.69 mmol) were added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with NaHCO3, extracted with DCM, and the organic layer was washed with water and brine. The mixture was dried with anhydrous Na2SO4, filtered, and concentrated to obtain crude intermediate CP3094-2.

[0321] MS m / z (ESI): 525.2 [M+1]

[0322] Step 2

[0323] Intermediate C3094-2 (90 mg, 0.17 mmol) was dissolved in methanol (2 mL) and water (1 mL), and LiOH (20.4 mg, 0.85 mmol) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the methanol was removed by rotary evaporation under reduced pressure. The pH was adjusted to 4-5 with 2 M dilute hydrochloric acid. The intermediate C3094-3 was obtained by purification by C18 reverse column chromatography.

[0324] MS m / z(ESI): 511.2 [M+1]

[0325] Step 3

[0326] Intermediate C3094-3 (10 mg, 0.02 mmol) and HATU (23 mg, 0.06 mmol) were dissolved in 1 mL of LDM in a dry 5 mL flask at room temperature. After dissolution, N-ethylethanolamine (5.5 mg, 0.06 mmol) and DIEA (13 mg, 0.1 mmol) were added. The resulting solution was stirred under nitrogen balloon protection at 40 °C until the reaction was complete. The reaction endpoint was detected by LCMS. The product CP3094 was obtained by preparative HPLC purification.

[0327] 1 ¹H NMR (400MHz, 6d-DMSO) δppm 9.38-9.27(m,1H),7.83-7.77(m,1H),7.31(s,1H),6.53(s,1H),5.63-5.58( m,1H),5.42(s,2H),5.30-5.27(m,2H),4.82-4.72(m,1H),3.60-3.52(m,2H) ,3.51-3.47(m,2H),3.40-3.33(m,2H),3.20-3.14(m,2H),2.24-2.17(m,2H) ,2.03-1.97(m,1H),1.90-1.82(m,2H),1.20-1.03(m,3H),0.89-0.83(m,3H).

[0328] Bioactivity test

[0329] Cell proliferation inhibition experiment

[0330] 1. Cell plating

[0331] 1) Prepare the complete culture medium and mix thoroughly.

[0332] 2) Resuscitate the cells. The cell growth characteristics, culture medium, and culture conditions are shown in the table below. Select cell lines in good growth condition after at least two passages.

[0333] 3) Transfer the cell suspension to a centrifuge tube using a pipette and centrifuge at 1000 rpm for 5 minutes. Discard the supernatant.

[0334] 4) Add an appropriate volume of culture medium to the centrifuge tube and gently pipette to resuspend the cells evenly.

[0335] 5) Use the Vi-Cell XR cell counter to count the cells.

[0336] 6) Adjust the cell suspension to the appropriate density using RPMI-1640 medium.

[0337] 7) Add the cell suspension to a 96-well plate at 190 μL / well, with a cell density of 1000 cells per well. Label the cell name, seeding density, date, and other details, and incubate the plate overnight in an incubator.

[0338] 2. Preparation and addition of compound plates:

[0339] Compound addition: On the second day after seeding, manually added compounds were prepared at 20X and stored, then diluted according to the appropriate ratio to prepare intermediate plates. 10 μL of the intermediate plate solution was added to the cell culture plate seeded the previous day. For DMSO compounds, the compound solution was added to the cell culture plate using an HPD300 autopilot. 0.1% DMSO was used as a control. The cell culture plate was then returned to the incubator for 72 or 144 hours of incubation.

[0340] 3. Detection and Analysis

[0341] 1) After 72 or 144 hours, remove the cell plate and observe the cell morphology and compound dissolution under an inverted microscope.

[0342] 2) Place the cell culture plate at room temperature for 30 minutes to equilibrate.

[0343] 3) Add 100 μL of Cell Titer Glo assay reagent to each well.

[0344] 4) Mix well on a vibrating plate for 15 minutes.

[0345] 5) Attach the white base film to the bottom of the culture plate and use the EnSpire plate.

[0346] 6) Record and analyze the experimental results.

[0347] 4. Data Analysis

[0348] 1) Calculate the inhibition rate and growth rate using the following formulas:

[0349] 1. Inhibition rate (%) = (1 - (RLU) compound -RLU blank ) / (RLU DMSO –RLU blank ))×100%.

[0350] 2. Survival rate (%Survival) (%) = ((RLU) compound -RLU blank ) / (RLU DMSO –RLU blank ))×100%.

[0351] 2) Use GraphPad Prism to plot the drug efficacy inhibition rate curve and calculate IC50.50 value.

[0352] IC 50 The concentration values ​​corresponding to a 50% inhibition rate under the curve fitted by GraphPad Prism 10 are shown in the table below:

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in, R 2 H, deuterium, halogen, NR n1 R n2 hydroxyl group, C 1-8 Alkyl or with one or more R 2-1 Replacement C 1-8 Alkyl; R 2-1 For deuterium, halogen, NR n1 R n2 or hydroxyl groups; Y is -LR 0 ;R 0 For OH or NR n3 R n4 ;R n3 and R n4 Independently H or C 1-8 alkyl; L is L 0 or -(L 1 -O) m -L 2 -; L 0 L 1 and L 2 Selected independently from C 1-8 alkylene or by one or more R c Replacement C 1-8 Alkylene; m is 1, 2, or 3; R c Independent of deuterium, halogen, NR n1 R n2 or hydroxyl groups; R n1 and R n2 Independently H or C 1-8 alkyl; R 1 R 3 The definition of X is as follows: Option 1: R 1 H, deuterium, halogen, NR n1 R n2 hydroxyl group, C 1-8 Alkyl or with one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 For deuterium, halogen, NR n1 R n2 or hydroxyl groups; R 3 For S or O; X is -CR x-1 R x-2 -、-O-、-S-、-P(=O)(OH)O-* or Ring A is a 4-10 membered heterocyclic alkyl group. In addition to the N atom attached to it, ring A contains 0, 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S; n is 0, 1, 2 or 3; and the * end is attached to Y. R b Halogen, deuterium, oxo group, hydroxyl group, NR n1 R n2 C 1-8 Alkyl, C 1-8 Alkyl groups or those with one or more R groups b-1 Replacement C 1-8 alkyl; R x-1 and R x-2 Independently for H and C 1-8 Alkyl or with one or more R x-1-1 Replacement C 1-8 Alkyl; or, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 cycloalkyl; R x-1-1 R a-1 and R b-1 Independent of deuterium, halogen, NR n1 R n2 or hydroxyl groups; R n1 and R n2 Independently H or C 1-8 alkyl; Option 2: R 1 H, deuterium, halogen, NR n1 R n2 hydroxyl group, C 1-8 Alkyl or with one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 For deuterium, halogen, NR n1 R n2 or hydroxyl groups; R 3 For S or O; X is -CR x-1 R x-2 -、-NR a -、-O-、-S-、-P(=O)(OH)O-* or Ring A is a 4-10 membered heterocyclic alkyl group. In addition to the N atom attached to it, ring A contains 0, 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S; n is 0, 1, 2 or 3; and the * end is attached to Y. R a For deuterium, C 1-8 Alkyl or with one or more R a-1 Replacement C 1-8 alkyl; R b Halogen, deuterium, oxo group, hydroxyl group, NR n1 R n2 C 1-8 Alkyl, C 1-8 Alkyl groups or those with one or more R groups b-1 Replacement C 1-8 alkyl; R x-1 and R x-2 Independently for H and C 1-8 Alkyl or with one or more R x-1-1 Replacement C 1-8 Alkyl; or, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 cycloalkyl; R x-1-1 R a-1 and R b-1 Independent of deuterium, halogen, NR n1 R n2 or hydroxyl groups; R n1 and R n2 Independently H or C 1-8 alkyl; Option 3: R 1 H, deuterium, halogen, NR n1 R n2 hydroxyl group, C 1-8 Alkyl or with one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 For deuterium, halogen, NR n1 R n2 or hydroxyl groups; R 3 S; X is -CR x-1 R x-2 -、-NH-、-NR a -、-O-、-S-、-P(=O)(OH)O-* or Ring A is a 4-10 membered heterocyclic alkyl group. In addition to the N atom attached to it, ring A contains 0, 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S; n is 0, 1, 2 or 3; and the * end is attached to Y. R a For deuterium, C 1-8 Alkyl or with one or more R a-1 Replacement C 1-8 alkyl; R b Halogen, deuterium, oxo group, hydroxyl group, NR n1 R n2 C 1-8 Alkyl, C 1-8 Alkyl groups or those with one or more R groups b-1 Replacement C 1-8 alkyl; R x-1 and R x-2 Independently for H and C 1-8 Alkyl or with one or more R x-1-1 Replacement C 1-8 Alkyl; or, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 cycloalkyl; R x-1-1 R a-1 and R b-1 Independent of deuterium, halogen, NR n1 R n2 or hydroxyl groups; R n1 and R n2 Independently H or C 1-8 alkyl; Option 4: R 1 H, deuterium, halogen, NR n1 R n2 hydroxyl group or one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 For deuterium, halogen, NR n1 R n2 or hydroxyl groups; R 3 For S or O; X is -CR x-1 R x-2 -、-NH-、-NR a -、-O-、-S-、-P(=O)(OH)O-* or Ring A is a 4-10 membered heterocyclic alkyl group. In addition to the N atom attached to it, ring A contains 0, 1, 2 or 3 heteroatoms selected from one, two or three of N, O and S; n is 0, 1, 2 or 3; and the * end is attached to Y. R a For deuterium, C 1-8 Alkyl or with one or more R a-1 Replacement C 1-8 alkyl; R b Halogen, deuterium, oxo group, hydroxyl group, NR n1 R n2 C 1-8 Alkyl, C 1-8 Alkyl groups or those with one or more R groups b-1 Replacement C 1-8 alkyl; R x-1 and R x-2 Independently for H and C 1-8 Alkyl or with one or more R x-1-1 Replacement C 1-8 Alkyl; or, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 cycloalkyl; R x-1-1 R a-1 and R b-1 Independent of deuterium, halogen, NR n1 R n2 or hydroxyl groups; R n1 and R n2 Independently H or C 1-8 alkyl.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) The C 1-8 Alkyl groups and the substituted C 1-8 The "C" in alkyl 1-8 "alkyl" is independently C 1-6 Alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and for example, methyl or ethyl; (2) The halogen is independently F, Cl, Br or I; for example F or Cl; or for example F; (3) The 4-10 membered heterocyclic alkyl group is a 4-8 membered heterocyclic alkyl group; for example, a 5-6 membered heterocyclic alkyl group; (4) In addition to the N atoms that are attached, ring A contains 0, 1, 2 or 3 N atoms; (5) In addition to the N atom it is attached to, ring A also contains 0, 1, 2, or 3 heteroatoms selected from one or two of N, O, and S; and, (6) The C 1-8 Alkyl groups are independently C 1-6 Alkyl groups; for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, and again, for example, methoxy or ethoxy.

3. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 2 It is a halogen; (2)R 0 It is OH; (3) L is L 0 ; (4)L 0 C 1-8 Alkylene; (5) In Scheme 1, R 1 C 1-8 alkyl; (6) In Scheme 1, R 3 For S or O; (7) In Scheme 1, X is -CR x-1 R x-2 -; (8) In Scheme 1, R x-1 and R x-2 Independently for C 1-8 Alkyl; for example, R x-1 and R x-2 Independently methyl; or, R x-1 R x- 2 Together with the C atoms they are attached to, they form C 3-6 Cycloalkyl; for example, R x-1 R x-2 Together with the C atoms they are attached to, they form cyclopropyl groups; (9) In Scheme 2, R 1 C 1-8 Alkyl or with one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 It is deuterium; (10) In Scheme 2, R 3 For S or O; (11) In Scheme 2, X is -NR a -; (12) In Scheme 2, R a C 1-8 Alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and for example, methyl or ethyl; (13) In Scheme 3, R 1 C 1-8 alkyl; (14) In Scheme 3, R 3 S; (15) In Scheme 3, X is -CR x-1 R x-2 -or-NR a -; (16) In Scheme 3, R a C 1-8 Alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and for example, methyl or ethyl; (17) In Scheme 3, R x-1 and R x-2 Independently for C 1-8 Alkyl; for example, R x-1 and R x-2 Independently methyl; or, R x-1 R x- 2 Together with the C atoms they are attached to, they form C 3-6 Cycloalkyl; for example, R x-1 R x-2 Together with the C atoms they are attached to, they form cyclopropyl groups; (18) In Scheme 4, R 1 For one or more R 1-1 Replacement C 1-8 Alkyl; R 1-1 It is deuterium; (19) In Scheme 4, R 3 For S or O; (20) In Scheme 4, X is -CR x-1 R x-2 -or-NR a -; (21) In Scheme 4, R a C 1-8 Alkyl groups; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and again, methyl or ethyl; and, (22) In Scheme 4, R x-1 R x-2 Together with the C atoms they are attached to, they form C 3-6 Cycloalkyl; for example, R x-1 R x-2 Together with the C atoms they are attached to, they form cyclopropyl groups.

4. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 It is methyl or trideuterated methyl; (2)R 2 For F; (3) X is and, (4) Y is 5. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It is a compound as shown in Formula I-1; Among them, R 0 L 0 R x-1 R x-2 R 1 R 2 and R 3 The definition is as described in any one of claims 1-4.

6. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It is a compound as shown in Formula I-2; Among them, R 0 L 0 R a R 1 R 2 and R 3 The definition is as described in any one of claims 1-4.

7. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It is a compound as shown in Formula I-3; Among them, R 0 L 0 X, R 1 and R 2 The definition is as described in any one of claims 1-4.

8. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It is a compound as shown in Formula I-4; Among them, R 0 L 0 X, R 1 and R 3 The definition is as described in any one of claims 1-4.

9. Any of the following compounds or their pharmaceutically acceptable salts:

10. A pharmaceutical composition comprising: (1) The compound of formula I as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or the compound of claim 9, or a pharmaceutically acceptable salt thereof; and, (2) Pharmaceutically acceptable excipients.

11. The use of a compound of Formula I as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof, a compound of claim 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 10 in the preparation of a medicament for treating tumors or tumor-related diseases.

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